Microglia: a cellular vehicle for CNS gene therapy

Abstract

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by deficiency of the enzyme arylsulfatase A (ARSA). MLD is characterized by progressive demyelination and neurological deficits. Treatment of MLD is still a challenge due to the fact that the blood-brain barrier is a major obstacle for most therapeutic substances. In this issue of the JCI, Biffi et al. report that genetically modified hematopoietic precursor cells transduced to overexpress ARSA and transplanted into mice with a targeted disruption of the murine Arsa gene (Arsa(-/-) mice) migrated into the CNS and cross-corrected brain ARSA deficiency (see the related article beginning on page 3070). Microglia served as a cellular vehicle to effectively deliver the enzyme to other brain cells while hepatocytes overexpressing ARSA increased plasma ARSA levels but failed to deliver ARSA into the CNS.

Figure 1. Comparison between the specialized capillaries of the CNS and those of other tissues.

(A) Capillaries of the CNS are continuous capillaries. The endothelial cells have tight junctions and are covered by astrocytic end feet. Small lipophilic molecules can passively pass through the BBB. Furthermore, certain molecules can actively pass the BBB using the carrier-mediated cell membrane transport system. (B) Capillaries of other tissues are often fenestrated, moderately porous capillaries (renal glomeruli, intestinal villi, and in most glands) or sinusoid, highly porous capillaries (in the liver, bone marrow, lymphoid tissues, and some endocrine organs). These ultramicroscopic pores are responsible for the majority of exchange between the blood and tissue. Furthermore, capillary exchange is executed by transcytosis, a process in which the endothelial cell encloses material of the bloodstream in an invagination of the cell membrane to form a vesicle, then moves the vesicle across the endothelium cell to eject the material at the tissue side.

Figure 2. In vivo versus ex vivo gene therapy.

(A) In vivo gene therapy is based on direct gene transfer into the cells requiring the replacement therapy. For CNS diseases, this implies direct injection of vectors into the CNS. (B) For ex vivo gene therapy, the gene transfer is performed in a cell type outside the body (e.g., blood cells), and the genetically modified cells are injected into the deficient recipient. The genetically modified cells can then circulate within the bloodstream, migrate through tissues, and deliver their therapeutic load to neighboring cells — a process known as cross-correction.